Vaccination is one of the most efficient methods to fight against infectious diseases. Over the last past 15 years, genetic engineering has allowed the precise identification of protein fragments that are responsible for the protective immune response and, as a result, new vaccination strategies have emerged. Immunization of animals with appropriate immunogenic peptides prompts the production of neutralizing antibodies that can control diseases. The expression of those immunogenic peptides in heterologous systems has provided the basis of subunit vaccines.
Although it has been demonstrated that chemically synthesized oligopeptides are capable of stimulating the production of antibodies against the protein from which they are derived, the peptides themselves have generally been found to be insufficiently immunogenic to serve as vaccines. Accordingly, there has been considerable interest in developing epitope-presentation systems, in which the peptide sequence is fused to a carrier molecule capable of assembly into a macromolecular structure.
Specific immunity can be enhanced by the use of immunopotentiators, such as adjuvants, when administering an antigen to a host. The immune response is mediated by a variety of cells in the immune system. There are two types of immune response: humoral immunity mediated by antibodies, and cellular immunity mediated primarily by cytotoxic T lymphocytes. Antigen presenting cells (“APC”) process and present antigen to both B and T cells. B cells secrete specific antibodies as a result of activation and T cells either become helper cells to the humoral response or cytotoxic cells and directly attack the antigen. Adjuvants have been shown to augment one or both of these immune responses.
Adjuvants are compounds which enhance the immune systems response when administered with antigen producing higher antibody titers and prolonged host response. Commonly used adjuvants include Incomplete Freund's Adjuvant (which consists of a water in oil emulsion), Freund's Complete Adjuvant (which comprises the above with the addition of Mycobacterium tuberculosis), and alum. The difficulty, however, in using these materials in humans, for example, is that they are toxic or may cause the host to develop lesions at the site of injection.
Carriers of immunogens of different natures that have been genetically engineered have been described. For example, cowpea mosaic virus (CPMV), tobacco mosaic virus X (TMVX), and alfalfa mosaic virus (AIMV) are known to having been modified for the presentation of epitopes of interest. Another plant viral vector, potato virus X (PVX), a member of the potexvirus group, is known to tolerate carriage of a complete protein overcoat. Also, U.S. Pat. Nos. 6,232,099 and 6,042,832, International Patent applications published under numbers WO 97/39134, WO 02/04007, WO 01/66778, WO 02/00169, and EP application 1167530, all describe different variations of virus-like particles carrying foreign proteins in fusion with endogenous proteins.
MHC class I and MHC class II associated antigen presentation is generally governed by two separate pathways. Endogenous antigens produced intracellularly reach the MHC class I pathway and prime for cytotoxic T cell (CTL) responses if presented by professional antigen presentation cells (APC). Induction of CTL responses is, therefore, usually confined to pathogens that replicate intracellularly. In contrast, T helper cell responses are primed by exogenous protein antigens, which reach the MHC class II pathway in professional APC (Braciale et al., 1987, Immunol. Rev. 98; 95-114; Heemels and Ploegh, 1995, Ann. Rev. Biochem. 64; 463-491; Yewdell et al., 1999, Immunol. Rev. 172; 97-108). These two pathways, however, are not completely separated and it is possible that exogenous antigens are presented in association with MHC class I molecules.
Certain virus-like particles (VLPs) have been reported to induce a CTL response even when they do not carry genetic information (Ruedl et al., 2002, Eur. J. Immunol. 32; 818-825; Storni, et al., 2002, J. Immunol., 168:2880-2886) and cannot actively replicate in the cells where they are invaginated. The cross-presentation of a VLP carrying an epitope from lymphocytic choriomeningitis virus by dendritic cells in vivo has been described (Ruedl et al., 2002, ibid). The ability of a VLP carrying an epitope from lymphocytic choriomeningitis virus (LCMV) to prime a CTL response has also been described, however, this VLP was unable to induce the CTL response when administered alone and failed to mediate effective protection from viral challenge. An effective CTL response was induced only when the VLP was used in conjunction with anti-CD40 antibodies or CpG oligonucleotides (Stomi, et al., 2002, ibid). An earlier report indicated that porcine parvovirus-like particles (PPMV) carrying a peptide from LCMV were able to protect mice against a lethal LCMV challenge (Sedlik, et al., 2000, J. Virol., 74:5769-5775).
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.